· Indication for cefepime, meropenem or piperacillin/tazobactam with < 24 hr therapy at time of assessment

· Expected ICU stay greater than 48 hrs

Exclusion criteria

· Receiving renal replacement therapy

· Impaired hepatic function (total bilirubin > 100umol/ml)

· Patients receiving palliative care

· Inadequate central venous catheter access

· Death was deemed imminent

Randomisation was performed using a computer program based on blocks of four with an allocation ratio of 1:1 stratified by participating sites.

Intervention

Each antibiotic dose was prepared by an on-duty, unblinded ICU pharmacist.

The dosing regimen was determined by the treating intensivist, with guidance from a local dosing protocol.

To ensure early achievement of therapeutic beta-lactam exposures in the intervention arm, a single loading dose infused over 30 min was given at initiation of antibiotic therapy meaning that the continuous infusion group received a larger antibiotic dose on day 1 post-randomisation compared to those in the control arm.

The study antibiotic was administered until (1) the treating intensivist decided to cease the drug; (2) the participant withdrew from the study; (3) ICU discharge; or (4) ICU death.

Outcomes and measurement

The primary endpoint

clinical cure at 14 days after antibiotic cessation

Clinical outcome was rated as either

(1) resolution: complete disappearance of all signs and symptoms related to infection;

(2) improvement: a marked or moderate reduction in disease severity and/or number of signs and symptoms related to infection;

(3) failure: insufficient lessening of the signs and symptoms of infection to qualify as improvement, death or indeterminate for any reason

Clinical cure was scored as a ‘‘Yes’’ for resolution and a ‘‘No’’ for all other findings (i.e. sum of 2 and 3 above)

Secondary endpoints

(1) PK/PD target attainment

(2) ICU-free days at day 28

(3) ventilator-free days at day 28

(4) survival at day 14

(5) survival at day 30

(6) time to white cell count (WCC) normalization

Sample size calculations

A sample size of 120 participants (60 in each treatment arm) was estimated to demonstrate a statistical significant difference in the primary endpoint (power 0.8, alpha 0.05). . For clinical cure, 75 % of patients in the intervention arm versus 45 % in the control arm were estimated to achieve clinical cure. The final study sample size was increased to 140 participants (70 in each arm) factoring in a 15–20 % dropout rate.

Actual enrolment

Participants were recruited from April 2013 to July 2014. Two hundred and twenty patients were assessed for eligibility of whom 140 were randomised and 134 received at least one dose of the study antibiotic. One hundred and twenty-six participants received 4 days of randomised treatment.

In the intervention group, loading dose of chosen antibiotic followed by Continuous infusion thereafter

6gm Cefepime over 24 hours

3g Meropenem over 24 hours

18g Piperacillin-tazobactam over 24 hours

In the control group, loading dose of the chosen antibiotic followed by

Cefepime - 2gm every 8 hrs

Meropenem - 1gm every 8 hrs

Piperacillin-Tazobactam - 4.5gm every 6 hrs

Stastistical analysis

Statistical analyses were primarily performed on the intention-to-treat (ITT) population. A modified intentionto-treat (mITT) analysis was also performed in all participants who received at least one dose of study antibiotic. A per-protocol (PP) analysis was performed in all participants who received study antibiotic for 4 days.

RESULTS

Outcome

The allocation of beta-lactam antibiotics was comparable between the treatment arms except for cefepime where 11 participants were allocated to the intervention arm and only two to the control arm.

The median 24-h antibiotic dose was not different between the intervention and control arms

The median antibiotic treatment course was 7 days (IQR 5–9) in both treatment arms.

The median ICU stay was 8 days (IQR 5–10) for participants in the intervention arm and 6 days (IQR 4–13) in the control arm (p = 0.544)

The median ventilator days were 6 (IQR 3–7) and 5 (IQR 3–11) for participants in the intervention and control arms (p = 0.662), respectively

The median ‘‘surrogate MIC’’ values were similar in both treatment arms: 8 mg/L (IQR 4–8) for cefepime, 2 mg/L (IQR 2–2) for meropenem, and 16 mg/L (IQR 8–16) for piperacillin/tazobactam

· CI administration demonstrated higher clinical cure rates than IB dosing in participants who had respiratory infection, participants who received

piperacillin/tazobactam and in those without concomitant antibiotic treatment.

Secondary outcome

. Differences in PK/PD target attainment rates were significantly higher in the intervention group at 100 % fT[MIC on day 1 and day 3 post-randomisation(97% in CI vs 68% in IB,p value<0.001).

. At 28 days, there was no difference in median ICU-free days but median ventilator-free days were significantly higher in the participants of the intervention

arm.

. There was no difference in survival at 14 days or 30 days between the treatment arms.

CONCLUSION

In critically ill patients with severe sepsis not receiving RRT, CI administration was associated with higher clinical cure rates and better PK/PD target attainment compared to IB dosing for three common beta-lactam antibiotics.

LIMITATION

Participants were only recruited from two centres in one country which may limit the generalizability of the findings to other treatment settings.

CI participants manifested higher median SOFA scores on admission compared to IB participants, it is possible that CI participants may have been selectively provided with additional monitoring in the ICU to account for their illness severity, which may influence clinical outcomes.

No follow up beyond ICU stay.

Exclusion of patients requiring RRT.

Take home message

Apart from patients on renal replacement therapy, sepsis patients should receive continous infusion of betalactams because of superior PK/PD profile over intermittent dosing.